P956: VALIDATION OF THE SECOND REVISION OF THE INTERNATIONAL STAGING SYSTEM (R2-ISS) FOR OVERALL SURVIVAL IN MULTIPLE MYELOMA IN A REAL WORLD COHORT: AN ANALYSIS BY THE BALKAN MYELOMA STUDY GROUP (BMSG)
Authors: Efstathios Kastritis, Eirini Katodritou, Sorina Badelita, Jelena Bila, Güldane Cengiz Seval, Zorica Cvetkovic, Daniel Coriu, Emmanouil Spanoudakis, Dimitra Dalampira, Aleksandra Sretenovic, Aggeliki Sevastoudi, Anca Bojan, Marko Mitrovic, Catalin Danaila, Maria Gavriatopoulou, Maria Roussou, Meletios A. Dimopoulos, Meral Beksac, Evangelos Terpos
Journal: HemaSphere (2023)

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: Multiple myeloma (MM) patients (pts) have heterogeneous outcomes. In 2015, the R-ISS was developed to combine ISS (based on serum albumin and b2 microglobulin) to with elevated serum LDH and cytogenetics associated with poor risk [del17p, t(4;14) & t(14;16)]. R-ISS provided a 3-group stratification but R-ISS classified ~60% of patients into the intermediate-risk category (R-ISS-2). In addition, the importance of +1q21 as a prognostic marker was established but was not included in R-ISS. A modification of the R-ISS (called R2-ISS) was developed to include ISS, serum LDH, del17p, t(4;14) and +1q21 by using the additive value of each risk feature. However, R2-ISS development was based only on data from newly diagnosed MM (NDMM) pts enrolled in clinical trials. Aims: to validate R2-ISS in a real-world population of patients with NDMM treated in centers of the Balkan Myeloma Study Group (BMSG). Methods: The study included 1503 pts with complete data for R2-ISS calculation in the BMSG registry. Results: median age of pts in the cohort was 66 years, 53% were >65 years and 53% were males. ISS stage was 1, 2 & 3 in 27%, 30% and 43% respectively, +1q21 was present in 25%, del17p in 13%, t(4;14) in 12% and t(14;16) in 7%; LDH>ULN was found in 20% of patients. Per R-ISS, 20%, 60% and 20% were stage 1, 2 & 3 respectively and per R2-ISS, 17% were low(I), 24% low-intermediate (II), 47% intermediate high (III) and 12% high risk (IV). This distribution was similar to the one in the original cohort (in which it was 19%, 31%, 41% and 9% respectively). Induction/1st line therapy was bortezomib-based in 44%, IMiD-based in 26% and bortezomib plus IMiD-based in 22%; 4% received anti-CD38 containing primary therapy. ASCT was given in 30% of the pts. The median follow-up of the cohort is 50 months. Median estimated OS for the four R2-ISS stages was 116, 104, 56 and 34 months respectively and 5-year OS rate was 76%, 70%, 48% and 38% (p<0.001)(Figure 1). However, OS was not significantly different between stage I & II groups (HR:1.148, p=0.349), but was significantly different for stage II vs III (p<0.001) and stage III vs IV vs high (p<0.001). We then evaluated R2-ISS in transplanted (median estimated OS of the four stages: 156, 178, 116 and 78 months) and non-transplanted patients (median estimated OS of the four stages: 80, 74, 47 and 19 months): again stage I and II groups had very similar outcomes. C-index for OS at 5 years was 0.693 (95% CI 0.652-0.734) (vs for R2-ISS and was 0.628 (95% CI 0.584-0.672) R-ISS; these were similar to C-index observed in the original cohorts (both in the training and validation sets). Among R-ISS-3 patients, 50% were rated as R2-ISS-IV and 50% as R2-ISS-III and compared to R-ISS, the R2-ISS could identify patients at higher risk (R-ISS-3 pts had median OS of 44 months vs 34 months for R2-ISS-IV). Among R-ISS-2 patients, 6% were R2-ISS-IV, 62% R2-ISS-III and 32% R2-ISS-II, discriminating different risk groups. Finally, among R-ISS-1 pts, 78% were R2-ISS-I and 22% R2-ISS-II. The above data indicate that R2-ISS discriminates more accurately patients at high risk, even among R-ISS-2 pts. Summary/Conclusion: R2-ISS provides a tool to identify more accurately patients at high risk who should probably be managed with more aggressive strategies or patients which should be prioritized for treatment in the setting of clinical trials of new drugs. The differences between the original cohort and BMSG cohort are probably explained by differences in a clinical trial vs a less selected real world population in our analysis.Keywords: Myeloma, Multiple myeloma